Insulin stimulates glucose uptake into muscle and adipose tissue through the translocation of the insulin-responsive glucose transporter type 4 (GLUT4) from an intracellular compartment to the cell surface. This laboratory has identified a novel pathway that plays a crucial role in the regulation of glucose uptake by insulin [Baumann et al., Nature 2000]. This pathway involves the insulin-stimulated tyrosine phosphorylation of the Cbl protooncogene, and its translocation to lipid raft microdomains of the plasma membrane via the multidomain adaptor protein CAP. Although CAP was cloned in the Saltiel laboratory several years ago, I have recently identified several CAP splicing isoforms from mouse adipose tissue with additional potential functional domains including a coiled-coil domain and a proline-rich region. I will examine the role of these domains in protein interactions, as well as the subcellular localization of the isoforms. I will explore the role of CAP isoforms in the CAPICbl pathway of insulin signal transduction, and examine the effects of mutant forms of these proteins on the regulation of glucose transport, glycogen synthesis and lipolysis by insulin. Finally, I will search for novel CAP-interacting proteins. This approach may lead to new insights into the molecular mechanisms of insulin action, and ultimately to therapeutic approaches to insulin resistance and diabetes. [unreadable] [unreadable]